TLDR
HDL dysfunction in T2D is a multi-faceted phenomenon in which HDL particles lose their normal atheroprotective functions — cholesterol efflux capacity, anti-inflammatory activity, anti-oxidative capacity, and vasoprotective effects — while potentially acquiring pro-inflammatory and pro-atherogenic properties.
Mechanisms
- Non-enzymatic glycation: Hyperglycemia drives AGE formation on apoA-I, impairing CEC and anti-inflammatory function. Glycated apoA-I fails to inhibit TNFα and IL-1β release from macrophages.
- Carbamylation: Increased MPO activity in T2D drives carbamylation of HDL, impairing SR-BI-dependent cholesterol efflux and inducing lipid droplet formation in macrophages.
- MPO-catalyzed oxidation: ApoA-I is a preferred target for MPO-catalyzed chlorination and nitration, impairing ABCA1-dependent cholesterol efflux and LCAT activation.
- Proteome remodeling: SAA enrichment converts HDL to pro-inflammatory; PON1 depletion reduces antioxidant capacity; loss of apoA-IV, apoE, apoM, apoF, apoJ, and PON3.
- Lipidome remodeling: TG enrichment, CE depletion, reduced sphingomyelins, plasmalogens, and S1P. Altered surface lipid architecture affects embedded protein function.
Functional Consequences
- Impaired reverse cholesterol transport → foam cell formation
- Reduced inhibition of VCAM-1/ICAM-1 → increased monocyte recruitment
- Impaired NO production → endothelial dysfunction
- Reduced protection against LDL oxidation → enhanced oxidative stress
- Pro-inflammatory HDL (SAA-enriched) → increased TNFα secretion from PBMCs
Contradictions
Some well-controlled T2D cohorts (Denimal et al. 2022) show preserved CEC and anti-inflammatory capacity despite classical lipidomic abnormalities, suggesting HDL dysfunction may be modifiable with glycemic control.